Triazine derivatives and their therapeutical applications

ABSTRACT

The invention provides for Triazine derivatives and their use to modulate protein kinase activity in a variety of conditions and diseases.

FIELD OF THE INVENTION

The present invention relates generally to the use of compounds to treata variety of disorders, diseases and pathologic conditions and morespecifically to the use of triazine compounds to modulate proteinkinases and for treating protein kinase-mediated diseases.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases, containing asimilar 250-300 amino acid catalytic domain, catalyze thephosphorylation of target protein substrates.

The kinases may be categorized into families by the substrates in thephosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids,etc.). Tyrosine phosphorylation is a central event in the regulation ofa variety of biological processes such as cell proliferation, migration,differentiation and survival. Several families of receptor andnon-receptor tyrosine kinases control these events by catalyzing thetransfer of phosphate from ATP to a tyrosine residue of specific cellprotein targets. Sequence motifs have been identified that generallycorrespond to each of these kinase families [Hanks et al., FASEB J.,(1995), 9, 576-596; Knighton et al., Science, (1991), 253, 407-414;Garcia-Bustos et al., EMBO J., (1994), 13:2352-2361). Examples ofkinases in the protein kinase family include, without limitation, ab1,Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2,CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK,EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4,FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck,Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, andZap70.

Studies indicated that protein kinases play a central role in theregulation and maintenance of a wide variety of cellular processes andcellular function. For example, kinase activity acts as molecularswitches regulating cell proliferation, activation, and/ordifferentiation. Uncontrolled or excessive kinase activity has beenobserved in many disease states including benign and malignantproliferation disorders as well as diseases resulting from inappropriateactivation of the immune system (autoimmune disorders), allograftrejection, and graft vs host disease.

It is reported that many diseases are associated with abnormal cellularresponses triggered by protein kinase-mediated events. These diseasesinclude autoimmune diseases, inflammatory diseases, bone diseases,metabolic diseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease andhormone-related diseases. In addition, endothelial cell specificreceptor PTKs, such as VEGF-2 and Tie-2, mediate the angiogenic processand are involved in supporting the progression of cancers and otherdiseases involving uncontrolled vascularization. Accordingly, there hasbeen a substantial effort in medicinal chemistry to find protein kinaseinhibitors that are effective as therapeutic agents.

One kinase family of particular interest is the Src family of kinases.Src kinase is involved in proliferation and migration responses in manycell types, cell activation, adhesion, motility, and survival, growthfactor receptor signaling, and osteoclast activation (Biscardi et al.,Adv. Cancer Res. (1999), 76, 61-119; Yeatman et al., Nat. Rev. Cancer(2004), 4, 470-480; Owens, D. W.; McLean et al., Mol. Biol. Cell (2000),11, 51-64), Members of the Src family include the following eightkinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk (Bolen etal., Annu. Rev. Immunol, (1997), 15, 371), These are nonreceptor proteinkinases that range in molecular mass from 52 to 62 kD. All arecharacterized by a common structural organization that is comprised ofsix distinct functional domains: Src homology domain 4 (SH4), a uniquedomain, SH3 domain, SH2 domain, a catalytic domain (SH1), and aC-terminal regulatory region [Brown et al., Biochem Biophys Acta (1996),1287, 121-149; Tatosyan et al. Biochemistry (Moscow) 2000, 65, 49-58).SH4 domain contains the myristylation signals that guide the Srcmolecule to the cell membrane. This unique domain of Src proteins isresponsible for their specific interaction with particular receptors andprotein targets (Thomas et al., Annu Rev Cell Dev Biol (1997), 13,513-609). The modulating regions, SH3 and SH2, control intra—as well asintermolecular interactions with protein substrates which affect Srccatalytic activity, localisation and association with protein targets(Pawson T., Nature (1995), 373, 573-580). The kinase domain, SH1, foundin all proteins of the Src family, is responsible for the tyrosinekinase activity and has a central role in binding of substrates. TheN-terminal half of Src kinase contains the site(s) for its tyrosinephosphorylation and regulates the catalytic activity of Src (Thomas etal., Annu Rev Cell Dev Biol (1997), 13: 513-609). v-Src differs fromcellular Src (c-Src) on the basis of the structural differences inC-terminal region responsible for regulation of kinase activity.

The prototype member of the Src family protein tyrosine kinases wasoriginally identified as the transforming protein (v-Src) of theoncogenic retrovirus, Rous sarcoma virus, RSV (Brugge et al., Nature(1977), 269, 346-348); Hamaguchi et al. (1995), Oncogene 10: 1637-1043).Viral v-Src is a mutated and activated version of a normal cellularprotein (c-Src) with intrinsic tyrosine kinase activity (Collett et al.,Proc Natl Acad Sci USA (1978), 75, 2021-2024). This kinasephosphorylates its protein substrates exclusively on tyrosyl residues(Hunter et al., Proc Natl Acad USA (1980), 77, 1311-1315).

Investigations indicated that Src is a cytoplasmic protein tyrosinekinase, whose activation and recruitment to perimembranal signalingcomplexes has important implications for cellular fate. It haswell-documented that Src protein levels and Src kinase activity aresignificantly elevated in human breast cancers (Muthuswamy et al.,Oncogene, (1995), 11, 1801-1810); Wang et al., Oncogene 6999), 18,1227-1237; Warmuth et al., Curr. Pharm. Des. (2003), 9, 2043-2059],colon cancers (Irby et al., Nat Genet (1999), 21, 187-190), pancreaticcancers (Lutz et al., Biochem Biophys Res Commun (1998), 243, 503-508],certain B-cell leukemias and lymphomas (Talamonti et al., J. Clin.Invest. (1993), 91, 53; Lutz et al., Biochem. Biophys. Res. (1998), 243,503; Biscardi et al., Adv. Cancer Res. (1999), 76, 61; Lynch et al.,Leukemia (1993), 7, 1416; Boschelli et al., Drugs of the Future (2000),25(7), 717), gastrointestinal cancer (Cartwright et al., Proc. Natl.Acad. Sci. USA, (1990), 87, 558-562 and Mao et al., Oncogene, (1997),15, 3083-3090), non-small cell lung cancers (NSCLCs) (Mazurenko at al.,European Journal of Cancer, (1992), 28, 372-7), bladder cancer (Fanninget al., Cancer Research, (1992), 52, 1457-62), oesophageal cancer(Jankowski et al., Gut, (1992), 33, 1033-8), prostate and ovarian cancer(Wiener et al., Clin. Cancer Research, (1999), 5, 2164-70), melanoma andsarcoma (Bohlen et al., Oncogene, (1993), 8, 2025-2031; Tatosyan et al.,Biochemistry (Moscow) (2000), 65, 49-58). Furthermore, Src kinasemodulates signal transduction through multiple oncogenic pathways,including EGFR, Her2/neu, PDGFR, FGFR, and VEGFR (Frame et al., Biochim.Biophys. Acta (2002), 1602, 114-130; Sakamoto et al., Jpn J Cancer Res,(2001), 92: 941-946).

Thus, it is anticipated that blocking signaling through the inhibitionof the kinase activity of Src will be an effective means of modulatingaberrant pathways that drive oncologic transformation of cells. Srckinase inhibitors may be useful anti-cancer agents (Abram et al., Exp.Cell Res., (2000), 254, 1). It is reported that inhibitors of src kinasehad significant antiproliferative activity against cancer cell lines (M.M. Moasser et al., Cancer Res., (1999), 59, 6145; Tatosyan et al.,Biochemistiy (Moscow) (2000), 65, 49-58).) and inhibited thetransformation of cells to an oncogenic phenotype (R. Karni et al.,Oncogene (1999), 18, 4654). Furthermore, antisense Src expressed inovarian and colon tumor cells has been shown to inhibit tumor growth(Wiener et al., Clin. Cancer Res., (1999), 5, 2164; Staley et al., CellGrowth Diff. (1997), 8, 269). Src kinase inhibitors have also beenreported to be effective in an animal model of cerebral ischemia (Paulet al. Nature Medicine, (2001), 7, 222), suggesting that Src kinaseinhibitors may be effective at limiting brain damage following stroke.Suppression of arthritic bone destruction has been achieved by theoverexpression of CSK in rheumatoid synoviocytes and osteoclasts(Takayanagi et al., J. Clin. Invest. (1999), 104, 137). CSK, orC-terminal Src kinase, phosphorylates and thereby inhibits Src catalyticactivity. This implies that Src inhibition may prevent joint destructionthat is characteristic in patients suffering from rheumatoid arthritis(Boschelli et al., Drugs of the Future (2000), 25(7), 717).

It is well documented that Src-family kinases are also important forsignaling downstream of other immune cell receptors. Fyn, like Lck, isinvolved in TCR signaling in T cells (Appleby et al., Cell, (1992), 70,751). Hck and Fgr are involved in Fey receptor signaling leading toneutrophil activation (Vicentini et al., J., Immunol. (2002), 168,6446). Lyn and Src also participate in Fcγ receptor signaling leading torelease of histamine and other allergic mediators (Turner, H. and Kinet,J-P Nature (1999), 402, B24). These-findings suggest that Src familykinase inhibitors may be useful in treating allergic diseases andasthma.

Other Src family kinases are also potential therapeutic targets. Lckplays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. The function of Lck as a positiveactivator of T-cell signaling suggests that Lck inhibitors may be usefulfor treating autoimmune disease such as rheumatoid arthritis (Molina etal., Nature, (1992), 357, 161).

Hck is a member of the Src protein-tyrosine kinase family and isexpressed strongly in macrophages, an important HIV target cell and itsinhibition in HIV-infected macrophages might slow disease progression(Ye et al., Biochemistry, (2004), 43 (50), 15775-15784).

Hck, Fgr and Lyn have been identified as important mediators of integrinsignaling in myeloid leukocytes (Lowell et al., J. Leukoc. Biol.,(1999), 65, 313). Inhibition of these kinase mediators may therefore beuseful for treating inflammation (Boschelli et al., Drugs of the Future(2000), 25(7), 717).

It is reported that Syk is a tyrosine kinase that plays a critical rolein the cell degranulation and eosinophil activation and Syk kinase isimplicated in various allergic disorders, in particular asthma (Tayloret al., Mol. Cell. Biol. (1995), 15, 4149).

BCR-ABL encodes the BCR-AEL protein, a constitutively active cytoplasmictyrosine kinase present in 90% of all patients with chronic myelogenousleukemia (CML) and in 15-30% of adult patients with acute lymphoblasticleukemia (ALL), Numerous studies have demonstrated that the activity ofBCR-ABL is required for the cancer causing ability of this chimericprotein.

Src kinases play a role in the replication of hepatitis B virus. Thevirally encoded transcription factor HBx activates Src in a steprequired for propagation of the virus (Klein et al., EMBO J. (1999), 18,5019; Klein et al., Mol. Cell. Biol. (1997), 17, 6427). Some genetic andbiochemical data clearly demonstrate that Src-family tyrosine kinasesserve as a critical signal relay, via phosphorylation of c-Cbl, for fataccumulation, and provide potential new strategies for treating obesity(Sun et al., Biochemistry, (2005), 44 (44), 14455-14462). Since Srcplays a role in additional signaling pathways, Src inhibitors are alsobeing pursued for the treatment of other diseases including osteoporosisand stroke (Susva et al., Trends Pharmacol. Sci. (2000), 21, 489-495;Paul et al., Nat. Med. (2001), 7, 222-227).

It is also possible that inhibitors of the Src kinase activity areuseful in the treatment of osteoporosis (Soriano et al., Cell (1991),64, 693; Boyce et al. J. Clin. Invest (1992), 90, 1622; Owens et al.,Mol. Biol. Cell (2000), 11, 51-64), T cell mediated inflammation(Anderson et al., Adv. Immunol. (1994), 56, 151; Goldman, F D et al. J.Clin. Invest. (1998), 102, 421), and cerebral ischemia (Paul et al.Nature Medicine (2001), 7, 222).

In addition, src family kinases participate in signal transduction inseveral cell types. For example, fyn, like Ick, is involved in T-cellactivation. Hck and fgr are involved in Fe gamma receptor mediatedoxidative burst of neutrophils. Src and lyn are believed to be importantin Fc epsilon induced degranulation of mast cells, and so may play arole in asthma and other allergic diseases. The kinase lyn is known tobe involved in the cellular response to DNA damage induced by UV light(Hiwasa et al., FEBS Lett. (1999), 444, 173) or ionizing radiation(Kumar et al., J Biol Chein, (1998), 273, 25654). Inhibitors of lynkinase may thus be useful as potentiators in radiation therapy.

T cells play a pivotal role in the regulation of immune responses andare important for establishing immunity to pathogens. In addition, Tcells are often activated during inflammatory autoimmune diseases, suchas rheumatoid arthritis, inflammatory bowel disease, type I diabetes,multiple sclerosis, Sjogren's disease, myasthenia gravis, psoriasis, andlupus. T cell activation is also an important component of transplantrejection, allergic reactions, and asthma.

T cells are activated by specific antigens through the T cell receptor,which is expressed on the cell surface. This activation triggers aseries of intracellular signaling cascades mediated by enzymes expressedwithin the cell (Kane et al. Current Opinion in Immunol. (2000), 12,242), These cascades lead to gene regulation events that result in theproduction of cytokines, like interleukin-2 (IL-2). is a necessarycytokine in T cell activation, leading to proliferation andamplification of specific immune responses.

Therefore, Src kinase other kinase have become an intriguing target fordrug discovery (Parang et al., Expert Opin. Ther. Pat. (2005), 15,1183-1207; Parang et al., Curr. Opin. Drug Discovery Dev. (2004), 7,630-638). Many classes of compounds have been disclosed to modulate or,more specifically, inhibit kinase activity for use to treatkinase-related conditions or other disorders. For example, U.S. Pat. No.6,596,746 and the PCT WO 05/096784A2 disclosed benzotrianes asinhibitors of kinases; the PCT WO 01/81311 disclosed substituted benzoicacid amides for the inhibition of angiogenisis; U.S. Pat. No. 6,440,965,disclosed substituted pyrimidine derivatives in the treatment ofneurodegenerative or neurological disorders; PCT WO 02/08205 reportedthe pyrimidine derivatives having neurotrophic activity; PCT WO03/014111 disclosed arylpiperazines and arylpiperidines and their use asmetalloproteinase inhibiting agents; PCT WO 03/024448 describedcompounds as inhibitors of histone deacetylase enzymatic activity; PCTWO 04/058776 disclosed compounds which possess anti-angiogenic activity.PCT WO 01/94341 and WO 02/16352 disclosed Src kinase inhibitors ofquinazoline derivatives. PCT WO03/026666A1 and WO03/018021A1 disclosedpyrimidinyl derivatives as kinase inhibitors. U.S. Pat. No. 6,498,165reported Src kinase inhibitor compounds of pyrimidine compounds.Peptides as Src Tyrosine Kinase Inhibitors is reported recently (Kumaret al., J. Med. Chem., (2006), 49 (11), 3395-3401). Thequinolinecarbonitriles derivatives was reported to be potent dualInhibitors of Src and Abl Kinases (Diane et al., J. Med. Chem., (2004),47 (7), 1599-1601).

Although a lot of inhibitors of kinases are reported, considering thelack of currently available treatment options for the majority of theconditions associated with protein kinases, there is still a great needfor new therapeutic agents that inhibit these protein targets.

SUMMARY OF THE INVENTION

Accordingly, it is an objective of the present invention to provide anantitumor agent comprising a triazine derivative as described in formula(I), pharmaceutically-acceptable formulations thereof, methods formaking novel compounds and methods and compositions for using thecompounds. The compounds and compositions comprising the compounds informula (I) have utility in treatment of a variety of diseases.

The combination therapy described herein may be provided by thepreparation of the triazine derivative of formula (I) and the othertherapeutic agent as separate pharmaceutical formulations followed bythe administration thereof to a patient simultaneously,semi-simultaneously, separately or over regular intervals.

The present invention provides methods of use for certain chemicalcompounds such as kinase inhibitors for treatment of various diseases,disorders, and pathologies, for example, cancer, and vascular disorders,such as myocardial infarction (MI), stroke, or ischemia. The triazinecompounds described in this invention may block the enzymatic activityof some or many of the members of the Src family, in addition toblocking the activity of other receptor and non-receptor kineses. Suchcompounds may be beneficial for treatment of the diseases wheredisorders affect cell motility, adhesion, and cell cycle progression,and in addition, diseases with related hypoxic conditions, osteoporosisand conditions, which result from or are related to increases invascular permeability, inflammation or respiratory distress, tumorgrowth, invasion, angiogenesis, metastases and apoptosis.

In another aspect of the invention are provided methods for modulatingSrc-family kinase activity comprising contacting the kinase with acompound of formula 1 in an amount sufficient to modulate the activityof the kinase. In some variation the activity of the kinase is reduced.In some variation the activity is inhibited.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to compounds showed as in Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R1 represents hydrogen, halogen, hydroxy, amino, cyano, alkyl,cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl, heterocyclic,heteroaryl, heterocycloalkyl, alkylsulfonyl, alkoxycarbonyl andalkylcarbonyl.

R2 is selected from:

(i) amino, alkyl amino, aryl amino, heteroaryl amino;

(ii) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;

(iii) heterocyclic, herteroaryl; and

(iv) groups of the formula (Ia):

wherein: X is CH, when R₄ is hydrogen; or X—R₄ is O or X is N when R₄represents groups.

R₃ is hydrogen, C₁-C₄ alkyl, oxo;

R₄ is chosen from: (a) hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₀ aryl or heteroaryl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₂-C₆ alkanoyl, C₁-C₆alkoxycarbonyl, C₂-C₆ alkanoyloxy, mono- and di-(C₃-C₈cycloalkyl)aminoC₀-C₄alkyl, (4- to 7-membered heterocycle)C₀-C₄alkyl,C₁-C₆ alkylsulfonyl, mono- and di-(C₁-C₆ alkyl) sulfonamido, and mono-and di-(C₁-C₆alkyl)aminocarbonyl, each of which is substituted with from0 to 4 substituents independently chosen from halogen, hydroxy, cyano,amino, —COOH and oxo;

L is selected from O, CO, (CH2)_(m), m=0-3, NR₁, CONR₁, NR₁CO, S, SO,SO2, O(CH₂)_(p), p=1-3, (CH2)_(q)O, n=1-3, cycloalkyl andheterocycloalkyl to link Ar₁ and Ar₂.

Ar₁, and Ar₂ independently are a heteroaryl or aryl, each of which issubstituted with from 0 to 4 substituents independently chosen from:

-   -   (1) halogen, hydroxy, amino, cyano, —COOH, —SO₂NH₂, oxo, nitro        and alkoxycarbonyl; and    -   (2) C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₆ alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        mono- and di-(C₁-C₆alkyl)amino, C₁-C₆ alkylsulfonyl, mono- and        di-(C₁-C₆alkyl) sulfonamido and mono- and        di-(C₁-C₆alkyl)aminocarbonyl; phenylC₀-C₄alkyl and (4- to        7-membered heterocycle)C₀-C₄alkyl, each of which is substituted        with from 0 to 4 secondary substituents independently chosen        from halogen, hydroxy, cyano, oxo, imino, C₁-C₄alkyl,        C₁-C₄alkoxy and C₁-C₄haloalkyl.

The following definitions refer to the various terms used above andthroughout the disclosure.

Compounds are generally described herein using standard nomenclature.For compounds having asymmetric centers, it should be understood that(unless otherwise specified) all of the optical isomers and mixturesthereof are encompassed. In addition, compounds with carbon-carbondouble bonds may occur in Z- and E-forms, with all isomeric forms of thecompounds being included in the present invention unless otherwisespecified. Where a compound exists in various tautomeric forms, arecited compound is not limited to any one specific tautomer, but ratheris intended to encompass all tautomeric forms. Certain compounds aredescribed herein using a general formula that includes, variables (e.g.X, Ar.). Unless otherwise specified, each variable within such a formulais defined independently of any other variable, and any variable thatoccurs more than one time in a formula is defined independently at eachoccurrence.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine oriodine.

The term “alkyl” herein alone or as part of another group refers to amonovalent alkane (hydrocarbon) derived radical containing from 1 to 12carbon atoms unless otherwise defined. Alkyl groups may be substitutedat any available point of attachment. An alkyl group substituted withanother alkyl group is also referred to as a “branched alkyl group”.Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl, and the like. Exemplary substituents include but are notlimited to one or more of the following groups: alkyl, aryl, halo (suchas F, Cl, Br, I), haloalkyl (such as CCl₃ or CF₃), alkoxy, alkylthio,hydroxy, carboxy (—COOH), alkyloxycarbonyl (—C(O)R), alkylcarbonyloxy(—OCOR), amino (—NH2), carbamoyl (—NHCOOR— or —OCONHR—), urea(—NHCONHR—) or thiol (—SH). In some preferred embodiments of the presentinvention, alkyl groups are substituted with, for example, amino,heterocycloalkyl, such as morpholine, piperazine, piperidine, azetidine,hydroxyl, methoxy, or heteroaryl groups such as pyrrolidine.

The term ‘cycloalkyl” herein alone or as part of another group refers tofully saturated and partially unsaturated hydrocarbon rings of 3 to 9,preferably 3 to 7 carbon atoms. The examples include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, and like. Further, a cycloalkylmay be substituted. A substituted cycloalkyl refers to such rings havingone, two, or three substituents, selected from the group consisting ofhalo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo(═O), hydroxy, alkoxy, thioalkyl, —CO2H, —C(═O)H, CO2-alkyl, C(═O)alkyl,keto, ═N—OH, ═N—O-alkyl, aryl, heteroaryl, heterocyclo, —NR′R″,C(═O)NR′R″, —CO2NR′R″, —C(═O)NR′R″, —NR′CO2R″, NR′C(═O)R″, —SO2NR′R″,and —NR′SO2R″, wherein each of R′ and R″ are independently selected fromhydrogen, alkyl, substituted alkyl, and cycloalkyl; or R′ and R″together form a heterocyclo or heteroaryl ring.

The term ‘alkenyl” herein alone or as part of another group refers to ahydrocarbon radical straight, branched or cyclic containing from 2 to 12carbon atoms and at least one carbon to carbon double bond. Examples ofsuch groups include the vinyl, allyl, 1-propenyl, isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 1-heptenyl, and like. Alkenyl groups may also besubstituted at any available point of attachment. Exemplary substituentsfor alkenyl groups include those listed above for alkyl groups, andespecially include C3 to C7 cycloalkyl groups such as cyclopropyl,cyclopentyl and cyclohexyl, which may be further substituted with, forexample, amino, oxo, hydroxyl, etc.

The term “alkynyl” refers to straight or branched chain alkyne groups,which have one or more unsaturated carbon-carbon bonds, at least one ofwhich is a triple bond. Alkynyl groups include C2-C8 alkynyl, C2-C6alkynyl and C2-C4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to4 carbon atoms, respectively. Illustrative of the alkynyl group includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, andhexenyl. Alkynyl groups may also be substituted at any available pointof attachment. Exemplary substituents for alkynyl groups include thoselisted above for alkyl groups such as amino, alkylamino, etc. Thenumbers in the subscript after the symbol “C” define the number ofcarbon atoms a particular group can contain.

The term “alkoxy” alone or as part of another group denotes an alkylgroup as described above bonded through an oxygen linkage (—O—).Preferred alkoxy groups have from 1 to 8 carbon atoms. Examples of suchgroups include the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,n-hexyloxy, cyclohexyloxy, n-heptyloxy, n-octyloxy and 2-ethylhexyloxy.

The term “alkylthio” refers to an alkyl group as described aboveattached via a sulfur bridge. Preferred alkoxy and alkylthio groups arethose in which an alkyl group is attached via the heteroatom bridge.Preferred alkylthio groups have from 1 to 8 carbon atoms. Examples ofsuch groups include the methylthio, ethylthio, n-propythiol,n-butylthiol, and like.

The term “oxo,” as used herein, refers to a keto (C═O) group. An oxogroup that is a substituent of a nonaromatic carbon atom results in aconversion of —CH2- to —C(═O)—.

The term “alkoxycarbonyl” herein alone or as part of another groupdenotes an alkoxy group bonded through a carbonyl group. Analkoxycarbonyl radical is represented by the formula: —C(O)OR, where theR group is a straight or branched. C1-C6 alkyl group, cycloalkyl, aryl,or heteroaryl.

The term “alkylcarbonyl” herein alone or as part of another group refersto an alkyl group bonded through a carbonyl group or —C(O)R.

The term “arylalkyl” herein alone or as part of another group denotes anaromatic ring bonded through an alkyl group (such as benzyl) asdescribed above.

The term “aryl” herein alone or as part of another group refers tomonocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyland the like, as well as groups which are fused, e.g., napthyl,phenanthrenyl and the like. An aryl group thus contains at least onering having at least 6 atoms, with up to five such rings being present,containing up to 20 atoms therein, with alternating (resonating) doublebonds between adjacent carbon atoms or suitable heteroatoms. Aryl groupsmay optionally be substituted with one or more groups including, but notlimited to halogen such as I, Br, F, or Cl; alkyl, such as methyl,ethyl, propyl, alkoxy, such as methoxy or ethoxy, hydroxy, carboxy,carbamoyl, alkyloxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino,cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O)m (m=O, 1, 2), or thiol.

The term “aromatic” refers to a cyclically conjugated molecular entitywith a stability, due to delocalization, significantly greater than thatof a hypothetical localized structure, such as the Kekule structure.

The term “amino” herein alone or as part of another group refers to—NH2. An “amino” may optionally be substituted with one or twosubstituents, which may be the same or different, such as alkyl, aryl,arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl or carboxyl.These substituents may be further substituted with a carboxylic acid,any of the alkyl or aryl substituents set out herein. In someembodiments, the amino groups are substituted with carboxyl or carbonylto form N-acyl or N-carbamoyl derivatives.

The term “alkylsulfonyl” refers to groups of the formula (SO2)-alkyl, inwhich the sulfur atom is the point of attachment. Preferably,alkylsulfonyl groups include C1-C6 alkylsulfonyl groups, which have from1 to 6 carbon atoms. Methylsulfonyl is one representative alkylsulfonylgroup.

The term “heteroatom” refers to any atom other than carbon, for example,N, O, or S.

The term “heteroaryl” herein alone or as part of another group refers tosubstituted and unsubstituted aromatic 5 or 6 membered monocyclicgroups, 9 or 10 membered bicyclic groups, and 11 to 14 memberedtricyclic groups which have at least one heteroatom (O, S or N) in atleast one of the rings. Each ring of the heteroaryl group containing aheteroatom can contain one or two oxygen or sulfur atoms and/or from oneto four nitrogen atoms provided that the total number of heteroatoms ineach ring is four or less and each ring has at least one carbon atom.

The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. The heteroaryl ring system may contain zero, one, twoor three substituents selected from the group consisting of halo, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxy,alkoxy, thioalkyl, —CO2H, —C(═O)H, —CO2-alkyl, —C(═O)alkyl, phenyl,benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substitutedcycloalkyl, heterocyclo, heteroaryl, —NR′R″, —C(═O)NR′R″, —CO2NR′R″,—C(═O)NR′R″, —NR′CO2R″, —NR′C(═O)R″, —SO2NR′R″, and —NR′SO2R″, whereineach of R′ and R″ is independently selected from hydrogen, alkyl,substituted alkyl, and cycloalkyl, or R′ and R″ together form aheterocyclo or heteroaryl ring.

Exemplary heteroaryl groups include acridinyl, azopanyl, azocinyl,benzimidazolyl, benzimidazolinyl, benzisothiazolyl, benzisoxazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, benzotriazolylcarbazolyl, benztetrazolyl, NH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,tetrahydrofuran, dihydroisoquinolinyl, dihydrotetrahydrofuranyl,1,4-dioxa-8-aza-spirodec-8-yl, dithiazinyl, furanyl, furazanyl,imidazolinyl, imidazolidinyl, imidazolyl, indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl,isoquinolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidinyl, piperidonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, pyridyl, pyrimidyl,pyrrolidinyl, pyrrolidonyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl,thianthrenyl, thiazolyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thienyl, thiophenyl, thiomorpholinyl and variantsthereof in which the sulfur atom is oxidized, triazinyl, xanthenyl andany of the foregoing that are substituted with from 1 to 4 substituentsas described above.

Preferably monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, diazolyl, isoxazolyl, thiazolyl,thiadiazolyl, S isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Preferably bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, dihydroisoindolyl,tetrahydroquinolinyl and the like.

Preferably tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “heterocycle” or “heterocycloalkyl” herein alone or as part ofanother group refers to a cycloalkyl group (nonaromatic) in which one ofthe carbon atoms in the ring is replaced by a heteroatom selected fromO, S or N. The “heterocycle” has from 1 to 3 fused, pendant or spirorings, at least one of which is a heterocyclic ring (i.e., one or morering atoms is a heteroatom, with the remaining ring atoms being carbon).The heterocyclic ring may be optionally substituted which means that theheterocyclic ring may be substituted at one or more substitutable ringpositions by one or more groups independently selected from alkyl(preferably lower alkyl), heterocycloalkyl, heteroaryl, alkoxy(preferably lower alkoxy), nitro, monoalkylamino (preferably a loweralkylamino), dialkylamino (preferably a alkylamino), cyano, halo,haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferablylower alkyl amido), alkoxyalkyl (preferably a lower alkoxy; loweralkyl), alkoxycarbonyl (preferably a lower alkylcarbonyloxy (preferablya lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups. Aheterocyclic group may generally be linked via any ring or substituentatom, provided that a stable compound results. N-linked heterocyclicgroups are linked via a component nitrogen atom.

Typically, a heterocyclic ring comprises 1-4 heteroatoms; within certainembodiments each heterocyclic ring has 1 or 2 heteroatoms per ring. Eachheterocyclic ring generally contains from 3 to 8 ring members (ringshaving from to 7 ring members are recited in certain embodiments), andheterocycles comprising fused, pendant or spiro rings typically containfrom 9 to 14 ring members which consists of carbon atoms and containsone, two, or three heteroatoms selected from nitrogen, oxygen and/orsulfur.

Examples of “heterocycle” or “heterocycloalkyl groups includepiperazine, piperidine, morpholine, thiomorpholine, pyrrolidine,imidazolidine and thiazolide.

The term “substituted heterocyclic” refers, for both aromatic andnon-aromatic structures, to heterocyclic groups further bearing one ormore substituents described above.

The term “substituent,” as used herein, refers to a molecular moietythat is covalently bonded to an atom within a molecule of interest. Forexample, a “ring substituent” may be a moiety such as a halogen, alkylgroup, haloalkyl group or other group discussed herein that iscovalently bonded to an atom (preferably a carbon or nitrogen atom) thatis a ring member.

The term “optionally substituted” as it refers that the heteroaryl orheterocyclyl group may be substituted at one or more substitutable ringpositions by one or more groups independently selected from alkyl(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,monoalkylamino (preferably with one to six carbons), dialkylamino(preferably with one to six carbons), cyano, halo, haloalkyl (preferablytrifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),alkoxyalkyl (preferably a lower alkoxy and lower alkyl), alkoxycarbonyl(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably alower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of t attachment for a substituent. For example, —CONH2is attached through the carbon atom.

The term “anticancer” agent includes any known agent that is useful forthe treatment of cancer including, but is not limited, Acivicin;Aclarubicin; Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin;Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide;Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin;Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide;Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; BleomycinSulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin;Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; CarubicinHydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin;Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine;Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine;Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel;Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; DroloxifeneCitrate; Dromostanolone Propionate; Duazomycin; Edatrexate; EflomithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized OilI 131; Etoposide; Etoposide Phosphate; Etoprine; FadrozoleHydrochloride; Fazarabine; Fenretinide; Floxuridine; FludarabinePhosphate; Fluorouracil; Fluorocitabine; Fosquidone; Fostriecin Sodium;Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea;Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; InterferonBeta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride;Lanreotide Acetate; Letrozole; Leuprolide Acetate; LiarozoleHydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride;Masoprocol; Maytansine; Mechlorethamine Hydrochloride; MegestrolAcetate; Melerigestrol Acetate; Melphalan; Menogaril; Mercaptopurine;Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide;Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper;Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole;Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan;Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium;Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safmgol;Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium;Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin;Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; TeloxantroneHydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; TopotecanHydrochloride; Toremifene Citrate; Trestolone Acetate; TriciribinePhosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide;Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate;Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate;Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and ZorubicinHydrochloride.

The term “kinase” refers to any enzyme that catalyzes the addition ofphosphate groups to a protein residue; for example, serine and threoninekineses catalyze the addition of phosphate groups to serine andthreonine residues.

The terms “Src kinase,” “Src kinase family,” and “Src family” refer tothe related homologs or analogs belonging to the mammalian family of Srckineses, including, for example, c-Src, Fyn, Yes and Lyn kineses and thehematopoietic-restricted kineses Hck, Fgr, Lck and Blk.

The term “therapeutically effective amount” refers to the amount of thecompound or pharmaceutical composition that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, e.g., restoration or maintenance of vasculostasis orprevention of the compromise or loss or vasculostasis; reduction oftumor burden; reduction of morbidity and/or mortality.

The term ‘pharmaceutically acceptable” refers to the fact that thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The terms “administration of a compound” or “administering a compound”refer to the act of providing a compound of the invention orpharmaceutical composition to the subject in need of treatment.

The term “protected” refers that the group is in modified form topreclude undesired side reactions at the protected site. Suitableprotecting groups for the compounds of the present invention will berecognized from the present application taking into account the level ofskill in the art, and with reference to standard textbooks, such asGreene, T. W. et al., Protective Groups in Organic Synthesis, John Wiley& Sons, New York (1999).

The term “pharmaceutically acceptable salt” of a compound recited hereinis an acid or base salt that is suitable for use in contact with thetissues of human beings or animals without excessive toxicity orcarcinogenicity, and preferably without irritation, allergic response,or other problem or complication. Such salts include mineral and organicacid salts of basic residues such as amines, as well as alkali ororganic salts of acidic residues such as carboxylic acids. Specificpharmaceutical salts include, but are not limited to, salts of acidssuch as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric,sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic,methanesulfonic, benzene sulfonic, ethane disulfonic,2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric,tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic,succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic,phenylacetic, alkanoic such as acetic, HOOC— (CH2)n-COOH where n is 0-4,and the like. Similarly, pharmaceutically acceptable cations include,but are not limited to sodium, potassium, calcium, aluminum, lithium andammonium. Those of ordinary skill in the art will recognize furtherpharmaceutically acceptable salts for the compounds provided herein. Ingeneral, a pharmaceutically acceptable acid or base salt can besynthesized from a parent compound that contains a basic or acidicmoiety by any conventional chemical method. Briefly, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, the use ofnonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol oracetonitrile, is preferred. It will be apparent that each compound ofFormula I may, but need not, be formulated as a hydrate, solvate ornon-covalent complex. In addition, the various crystal forms andpolymorphs are within the scope of the present invention. Also providedherein are prodrugs of the compounds of Formula I.

The term of “prodrug” refers a compound that may not fully satisfy thestructural requirements of the compounds provided herein, but ismodified in vivo, following administration to a patient, to produce acompound of Formula I, or other formula provided herein. For example, aprodrug may be an acylated derivative of a compound as provided herein.Prodrugs include compounds wherein hydroxy, amine or thiol groups arebonded to any group that, when administered to a mammalian subject,cleaves to form a free hydroxy, amino, or thiol group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol and amine functional groups withinthe compounds provided herein. Prodrugs of the compounds provided hereinmay be prepared by modifying functional groups present in the compoundsin such a way that the modifications are cleaved in vivo to yield theparent compounds.

Groups that are “optionally substituted” are unsubstituted or aresubstituted by other than hydrogen at one or more available positions.Such optional substituents include, for example, hydroxy, halogen,cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy,C2-C6 alkyl ether, C3-C6 alkanone, C2-C6 alkylthio, amino, mono- ordi-(C1-C6 alkyl)amino, C1-C6 haloalkyl, —COOH, —CONH2, mono- ordi-(C1-C6 alkyl)aminocarbonyl, —SO2NH2, and/or mono or di(C1-C6alkyl)sulfonamido, as well as carbocyclic and heterocyclic groups.

Optional substitution is also indicated by the phrase “substituted withfrom 0 to X substituents,” where X is the maximum number of possiblesubstituents. Certain optionally substituted groups are substituted withfrom 0 to 2, 3 or 4 independently selected substituents.

Preferred Ar1 groups of formula I are list below, wherein the substitutemay be the specific ones as defined here or may be one or multiplesubstitutes as defined above:

Preferred Ar2 groups of formula I are list below, wherein the substitutemay be the specific ones as defined here or may be one or multiplesubstitutes as defined above:

Preferred R1 groups of formula I are list below:

—CH3, —CN, —CF3, —CH2CH3, -Ph, -PhCl, -PhOMe,

Preferred L is selected from O, CO, (CH2)m, m=0-2, NR1, CONR1, NR1CO, S,SO, SO2, O(CH2)p, p=1-2, (CH2)qO, q=1-2, cycloalkyl and heterocycloalkylto link Ar1 and Ar2.

Preferred R2 groups of formula I are list below:

Preferably, the compounds of the invention may be compounds of formula(I) wherein

R1 is selected from amino, cyano, C1-C6 alkyl, C-C6 alkoxy,C3-C6cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl C2-C6 alkanoyl, C1-C6haloalkyl, C1-C6 haloalkoxy, mono- and di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- and di-(C1-C6alkyl)sulfonamido and mono- anddi-(C1-C6alkyl)aminocarbonyl;

R2 is selected from:

(i) amino, alkyl amino, aryl amino, heteroaryl amino;

(ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

(iii) heterocyclic, herteroaryl; and

(iv) groups of the formula:

wherein: X is CH, when R4 is hydrogen; or X—R4 is 0; or X is N when R4represents groups.

R3 is hydrogen, C1-C4 alkyl, oxo;

R4 is chosen from: (a) hydrogen, C1-06 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C10 aryl or heteroaryl, (C3-C7cycloalkyl)C1-C4alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkanoyl, C1-C6alkoxycarbonyl, C2-C6 alkanoyloxy, mono- and di-(C3-C8cycloalkyl)aminoC0-C4alkyl, (4- to 7-membered heterocycle)C0-C4alkyl,C1-C6 alkylsulfonyl, mono- and di-(C1-C6 alkyl) sulfonamido, and mono-and di-(C1-C6alkyl)aminocarbonyl, each of which is substituted with from0 to 4 substituents independently chosen from halogen, hydroxy, cyano,amino, —COOH and oxo;

L is selected from O, CO, (CH2)m, m=0-3, NR1, CONR1, NR1CO, S, SO, SO2,O(CH2)p, p=1-3, (CH2)qO, q=1-3, cycloalkyl and heterocycloalkyl to linkAr1 and Ar2.

Ar1 and Ar2 are independently a heteroaryl or aryl, each of which issubstituted with from 0 to 4 substituents independently chosen from:

-   -   (1) halogen, hydroxy, amino, cyano, —COON, —SO2NH2, oxo, nitro        and aminocarbonyl; and    -   (2) C1-C6 alkyl, C-C6alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl,        C2-C6 alkynyl C2-C6 alkanoyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,        mono- and di-(C1-C6alkyl)amino, C1-C6 alkylsulfonyl, mono- and        di-(C1-C6alkyl)sulfonamido and mono- and        di-(C1-C6alkyl)aminocarbonyl; phenylC0-C4alkyl and (4- to        7-membered heterocycle)C0-C4alkyl, each of which is substituted        with from 0 to 4 secondary substituents independently chosen        from halogen, hydroxy, cyano, oxo, amino, C0-C4alkyl,        C1-C4alkoxy and C1-C4haloalkyl.

More preferably, the compounds of the invention may be compounds offormula (I) wherein

R1 is selected from cyano, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 aryl;

R2 is selected from a heterocyclic, herteroaryl or groups of the formula(Ia):

wherein: X is CH, when R4 is hydrogen; X is N for other R4 groups.

R3 is hydrogen, C1-C4 alkyl, oxo;

R4 is chosen from: C3-C10 aryl or heteroaryl,(C3-C7cycloalkyl)C1-C4alkyl, mono- and di-(C3-C8cycloalkyl)aminoC0-C4alkyl, (4- to 7-membered heterocycle)C0-C4alkyl,C1-C6 alkylsulfonyl, mono- and di-(C1-C6 alkyl)sulfonamido;

L is selected from O, CO, (CH2)m, m=0-3, NR1, CONR1, NR1CO, S, SO, SO2,O(CH2)p, p=1-3, (CH2)qO, n=1-3, cycloalkyl and heterocycloalkyl to linkAr1 and Ar2.

Ar1 and Ar2 are independently a heteroaryl or aryl, each of which issubstituted with from 0 to 4 substituents independently chosen from:

-   -   (1) halogen, hydroxy, amino, cyano, —COON, —SO2NH2, oxo, nitro        and aminocarbonyl; and    -   (2) C1-C6 alkyl, C-C6alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl,        C2-C6 alkynyl C2-C6 alkanoyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,        mono- and di-(C1-C6alkyl)amino, C1-C6 alkylsulfonyl, mono- and        di-(C1-C6alkyl)sulfonamido and mono- and        di-(C1-C6alkyl)aminocarbonyl; phenylC0-C4alkyl and (4- to        7-membered heterocycle)C0-C4alkyl, each of which is substituted        with from 0 to 4 secondary substituents independently chosen        from halogen, hydroxy, cyano, oxo, imino, C0-C4alkyl,        C1-C4alkoxy and C1-C4haloalkyl.

Most preferably R4 is (CH2)nY, n is integer 0 to 4, Y is selected frommorpholin-4-yl, thiomorpholin-4-yl, pyridinyl, pirimidinyl, piperidinyl,piperazinyl, or pyrrolidinyl.

According to one embodiment, the present invention relates to a compoundof formula I wherein Ar1 is thioazolyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is pyridyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is pyrimidinyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is pyrazinyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is imidazolyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is benzothioazolyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is benzo[1,2,4]triazinyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar1 is phenyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar2 is 2-methyl-6-chloro-phenyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar2 is 2,6-dichlorophenyl.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar2 is 2,6-dimethylphenyl.

According to another embodiment, the present invention relates to acompound of formula I wherein R1 is methyl.

According to another embodiment, the present invention relates to acompound of formula I wherein R1 is ethyl.

According to another embodiment, the present invention relates to acompound of formula I wherein R1 is trifloromethyl.

According to another embodiment, the present invention relates to acompound of formula I wherein R1 is CN.

According to another embodiment, the present invention relates to acompound of formula I wherein R1 is phenyl.

According to another embodiment, the present invention relates to acompound of formula I wherein L is oxygen.

According to another embodiment, the present invention relates to acompound of formula I wherein L is CO.

According to another embodiment, the present invention relates to acompound of formula I wherein L is NHCO.

According to another embodiment, the present invention relates to acompound of formula I wherein L is CONH.

According to another embodiment, the present invention relates to acompound of formula I wherein L is NH.

According to another embodiment, the present invention relates to acompound of formula I wherein L is S.

According to another embodiment, the present invention relates to acompound of formula I wherein L is SO.

According to another embodiment, the present invention relates to acompound of formula I wherein L is SO2.

According to another embodiment, the present invention relates to acompound of formula I wherein Ar2-L-Ar1-NH2 is:

Examples of specific compounds of the present invention are thosecompounds defined in the following:

In another embodiment, a method of preparing the inventive compounds isprovided. The compounds of the present invention can be generallyprepared using cyanuric chloride as a starting material. Compound (I)may contain various stereoisomers, geometric isomers, tautomericisomers, and the like. All of possible isomers and their mixtures areincluded in the present invention, and the mixing ratio is notparticularly limited.

The triazine derivative compounds of Formula (I) in this invention canbe prepared by known procedure in the prior art. The examples could befound in US patent No. 2005250945A1; US patent No. 20050227983A1; PCT WO05/007646A1; PCT WO 05/007648A2; PCT WO 05/003103A2; PCT WO 05/011703A1; and J. of Med. Chem. (2004), 47(19), 4649-4652. Starting materialsare commercially available from suppliers such as Sigma-Aldrich Corp.(St. Louis, Mo.), or may be synthesized from commercially availableprecursors using established protocols. By way of example, a syntheticroute similar to that shown in any of the following Schemes may be used,together with synthetic methods known in the art of synthetic organicchemistry, or variations thereon as appreciated by those skilled in theart. Each variable in the following schemes refers to any groupconsistent with the description of the compounds provided herein.

In the Schemes that follow the term “reduction” refers to the process ofreducing a nitro functionality to an amino functionality, or the processof transforming an ester functionality to an alcohol. The reduction of anitro group can be carried out in a number of ways well known to thoseskilled in the art of organic synthesis including, but not limited to,catalytic hydrogenation, reduction with SnCI2 and reduction withtitanium bichloride. The reduction of an ester group is typicallyperformed using metal hydride reagents including, but not limited to,diisobutyl-aluminum hydride (DIBAL), lithium aluminum hydride (LAH), andsodium borohydride. For an overview of reduction methods see: Hudlicky,M. Reductions in Organic Chemistry, ACS Monograph 188, 1996. In theSchemes that follow, the term “hydrolyze” refers to the reaction of asubstrate or reactant with water. More specifically, “hydrolyze” refersto the conversion of an ester or nitrite functionality into a carboxylicacid. This process can be catalyzed by a variety of acids or bases wellknown to those skilled in the art of organic synthesis.

The compounds of Formula I may be prepared by use of known chemicalreactions and procedures. The following general preparative methods arepresented to aid one of skill in the art in synthesizing the inhibitors,with more detailed examples being presented in the experimental sectiondescribing the working examples.

Heterocyclic amines are defined in formula II, wherein Ar₁ isheteroaryl. Some of heterocyclic amines are commercially available,others may be prepared by known procedure in the prior art (e.g., U.S.Patent 2006/0004067 A1; J. Med. Chem. 2004, 47, 6658-6661; World patentNo. WO 99/32106; Katritzky, et al. Comprehensive Heterocyclic Chemistry;Permagon Press: Oxford, UK, 1984, March. Advanced Organic Chemistry,3^(rd) Ed.; John Wiley: New York, 1985).

For example, 2-amino-N-(substituted aryl)thiazole-5-carboxamide (B) areavailable by the reaction of thiourea with a substitutedphenyl-3-ethoxyacrylamide (A) in the presence of NBS, as illustrated inScheme 1. Compound B, in turn, can be made from the reaction of3-ethyoxyacryloyl chloride with an substituted aniline Ar₂—NH₂

Substituted anilines may be generated using standard methods (March, J.,Advanced Organic Chemistry, 4^(th) Ed., John Wiley, New York (1992);Larock, R., Comprehensive Organic Transformations; John Wiley, New York(1999); PCT WO 99/32106). As shown in Scheme 2, aryl amines are commonlysynthesized by reduction of nitroaryls using a metal catalyst, such asNi, Pd, or Pt, and H₂ or a hydride transfer agent, such as formate,cyclohexadiene, or a borohydride. Nitroaryls may also be directlyreduced using a strong hydride source, such as LiAlH, or using a zerovalent metal, such as Fe, Sri or Ca, often in acidic media. Many methodsexist for the synthesis of nitroaryls.

Nitroaryls are commonly formed by electrophilic aromatic nitration usingHNO₃, or an alternative NO₂ ⁺ source. Nitroaryls may be furtherelaborated prior to reduction.

Thus, nitroaryls substituted with potential leaving groups (eg. F, Cl,Br, etc.) may undergo substitution reactions on treatment withnucleophiles, such as thiolate (exemplified in Scheme 3) or phenoxide.Nitroaryls may also undergo Ullman-type coupling reactions (Scheme 3).

Scheme 4 illustrated the one of the method to prepare those anilines asin Formula II, where L is carbonyl. These anilines are readily availablefrom reactions of an aniline with a substituted aryl carbonyl chloride,Acetyl protection of the amine, which can be easily removed after theFriedel-Crafts reaction, is preferred. These carbonyl linked anilinescan be further converted to methylene or hydroxyl methylene linked onesby appropriate reduction.

The preparation of compounds in formula (III) of this invention can becarried out by methods known in the art (e.g., J. Med. Chem. 1996, 39,4354-4357; J. Med. Chem. 2004, 47, 600-611; J. Med. Chem. 2004, 47,6283-6291; J. Med. Chem. 2005, 48, 1717-1720; J. Med. Chem. 2005, 48,5570-5579; U.S. Pat. No. 6,340,683 B1).

wherein R₁, is allyl or aryl, R_(a), R_(b), are substituted alkyl, aryl,or other substituents; Ar₁, L, and Ar₂ are defined as in formula (I).

As shown in Scheme 4, triazine derivatives can be formed from thereaction of a 6-alkyl or aryl substituted dichloro-triazine with an arylamine (Ar2-L-Ar1-NH2), followed by reaction with a substituted amine(HNR_(a)R_(b)). The 6-alkyl or aryl substituted dichloro-triazine may besynthesized by the methods known in the art (e.g., J. Med. Chem. 1999,42, 805-818 and J. Med. Chem. 2004, 47, 600-611). Alternatively, thereaction of cyanuric chloride with Grignard reagent generally canproduce 2,4-dichloro-6-R₁-1,3,5-triazine in high yield. Triazinederivatives also can be generated from the reaction of a substitutedamine (HNR_(a)R_(b)), followed by reaction with an aryl amine(Ar₂-L-Ar₁—NH2).

As shown in scheme 5, the triazine derivative can also be synthesized bythe reaction of cyanuric chloride with a sequence of two differentamines to give 2,4-disubstituted-6-chloro-1,3,5-tiazines. Thedisplacement of the last chlorine by amine, hydrazine, hydroxyl or othernucleophilic group can be achieved by increasing the temperature,affording the trisubstituted-1,3,5-triazines.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −50° C. to 100° C.

The present invention provides compositions of matter that areformulations of one or more active drugs and apharmaceutically-acceptable carrier. In this regard, the inventionprovides a composition for administration to a mammalian subject, whichmay include a compound of formula I, or its Pharmaceutically acceptablesalts.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN+(C1-4 alkyl)4 salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, troches, elixirs, suspensions,syrups, wafers, chewing gums, aqueous suspensions or solutions.

The oral compositions may contain additional ingredients such as: abinder such as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such starch or lactose, a disintegrating agent such as alginicacid, corn starch and the like; a lubricant such as magnesium stearate;a glidant such as colloidal silicon dioxide; and a sweetening agent suchas sucrose or saccharin or flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may additionally contain a liquid carrier such as a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, such as, for example, a coating. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the activeingredients, sucrose as a sweetening agent and certain preservatives,dyes and colorings and flavors. Materials used in preparing thesevarious compositions should be pharmaceutically or veterinarally pureand non-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activeingredient may be incorporated into a solution or suspension. Thesolutions or suspensions may also include the following components: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The pharmaceutical forms suitable for injectable use include sterilesolutions, dispersions, emulsions, and sterile powders. The final formshould be stable under conditions of manufacture and storage.Furthermore, the final pharmaceutical form should be protected againstcontamination and should, therefore, be able to inhibit the growth ofmicroorganisms such as bacteria or fungi. A single intravenous orintraperitoneal dose can be administered. Alternatively, a slowlong-term infusion or multiple short-term daily infusions may beutilized, typically lasting from 1 to 8 days. Alternate day dosing ordosing once every several days may also be utilized.

Sterile, injectable solutions may be prepared by incorporating acompound in the required amount into one or more appropriate solvents towhich other ingredients; listed above or known to those skilled in theart, may be added as required. Sterile injectable solutions may beprepared by incorporating the compound in the required amount in theappropriate solvent with various other ingredients as required.Sterilizing procedures, such as filtration, may then follow. Typically,dispersions are made by incorporating the compound into a sterilevehicle which also contains the dispersion medium and the required otheringredients as indicated above. In the case of a sterile powder, thepreferred methods include vacuum drying or freeze drying to which anyrequired ingredients are added.

Suitable pharmaceutical carriers include sterile water; saline,dextrose; dextrose in water or saline; condensation products of castoroil and ethylene oxide combining about 30 to about 35 moles of ethyleneoxide per mole of castor oil; liquid acid; lower alkanols; oils such ascorn oil; peanut oil, sesame oil and the like, with emulsifiers such asmono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin,and the like; glycols; polyalkylene glycols; aqueous media in thepresence of a suspending agent, for example, sodiumcarboxymethylcellulose; sodium alginate; poly(vinylpyrolidone); and thelike, alone, or with suitable dispensing agents such as lecithin;polyoxyethylene stearate; and the like. The carrier may also containadjuvants such as preserving stabilizing, wetting, emulsifying agentsand the like together with the penetration enhancer. In all cases, thefinal form, as noted, must be sterile and should also be able to passreadily through an injection device such as a hollow needle. The properviscosity may be achieved and maintained by the proper choice ofsolvents or excipients. Moreover, the use of molecular or particulatecoatings such as lecithin, the proper selection of particle size indispersions, or the use of materials with surfactant properties may beutilized.

In accordance with the invention, there are provided compositionscontaining triazine derivatives and methods useful for the in vivodelivery of triazine derivatives in the form of nanoparticles, which aresuitable for any of the aforesaid routes of administration.

U.S. Pat. Nos. 5,916,596, 6,506,405 and 6,537,579 teach the preparationof nanoparticles from the biocompatible polymers, such as albumin. Thus,in accordance with the present invention, there are provided methods forthe formation of nanoparticles of the present invention by a solventevaporation technique from an oil-in-water emulsion prepared underconditions of high shear forces (e.g., sonication, high pressurehomogenization, or the like).

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticallyacceptable compositions may be formulated in an ointment such aspetrolatum.

The pharmaceutically acceptable compositions of this invention may alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

In accordance with the invention, the compounds of the invention may beused to treat diseases associated with cellular proliferation orhyperproliferation, such as cancers which include but are not limited totumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity,oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas.The compounds of the invention may also be used to treat cancers of theliver and biliary tree (particularly hepatocellular carcinoma),intestinal cancers, particularly colorectal cancer, ovarian cancer,small cell and non-small cell lung cancer, breast cancer, sarcomas(including fibrosarcoma, malignant fibrous histiocytoma, embryonalrhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, osteosarcoma,synovial sarcoma, liposarcoma, and alveolar soft part sarcoma),neoplasms of the central nervous systems (particularly brain cancer),and lymphomas (including Hodgkin's lymphoma, lymphoplasmacytoidlymphoma, follicular lymphoma, mucosa-associated lymphoid tissuelymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt'slymphoma, and T-cell anaplastic large cell lymphoma).

The compounds and methods of the present invention, either whenadministered alone or in combination with other agents (e.g.,chemotherapeutic agents or protein therapeutic agents described below)are also useful in treating a variety of disorders, including but notlimited to, for example: stroke, cardiovascular disease, myocardialinfarction, congestive heart failure, cardiomyopathy, myocarditis,ischemic heart disease, coronary artery disease, cardiogenic shock,vascular shock, pulmonary hypertension, pulmonary edema (includingcardiogenic pulmonary edema), pleural effusions, rheumatoid arthritis,diabetic retinopathy, retinitis pigmentosa, and retinopathies, includingdiabetic retinopathy and retinopathy of prematurity, inflammatorydiseases, restenosis, asthma, acute or adult respiratory distresssyndrome (ARDS), lupus, vascular leakage, protection from ischemic orreperfusion injury such as ischemic or reperfusion injury incurredduring organ transplantation, transplantation tolerance induction;ischemic or reperfusion injury following angioplasty; arthritis (such asrheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiplesclerosis; inflammatory bowel disease, including ulcerative colitis andCrohn's disease; lupus (systemic lupus crythematosis); graft vs. hostdiseases; T-cell mediated hypersensitivity diseases, including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); Type 1 diabetes; psoriasis; contactdermatitis (including that due to poison ivy); Hashimoto's thyroiditis;Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves' disease;Addison's disease (autoimmune disease of the adrenal glands); autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome);autoimmune alopecia; pernicious anemia; vitiligo; autoimmunehypopituatarism; Guillain-Barre syndrome; other autoimmune diseases;cancers, including those where kineses such as Src-family kineses areactivated or overexpressed, such as colon carcinoma and thymoma, orcancers where kinase activity facilitates tumor growth or survival;glomerulonephritis, serum sickness; uticaria; allergic diseases such asrespiratory allergies (asthma, hayfever, allergic rhinitis) or skinallergies; mycosis fungoides; acute inflammatory responses (such asacute or adult respiratory distress syndrome and ischemialreperfusioninjury); dermatomyositis; alopecia areata; chronic actinic dermatitis;eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum;Sezary's syndrome; atopic dermatitis; systemic schlerosis; morphea;peripheral limb ischemia and ischemic limb disease; bone disease such asosteoporosis, osteomalacia, hyperparathyroidism, Paget's disease, andrenal osteodystrophy; vascular leak syndromes, including vascular leaksyndromes induced by chemotherapies or immunomodulators such as IL-2;spinal cord and brain injury or trauma; glaucoma; retinal diseases,including macular degeneration; vitreoretinal disease; pancreatitis;vasculatides, including vasculitis, Kawasaki disease, thromboangiitisobliterans, Wegener s granulomatosis, and Behcet's disease; scleroderma;preeclampsia; thalassemia; Kaposi's sarcoma; von Hippel Lindau disease;and the like.

In accordance with the invention, the compounds of the invention may beused to treat diseases associated with undesired cellular proliferationor hyperproliferation comprising identifying the mammal afflicted withsaid disease or condition and administering to said afflicted mammal acomposition comprising the compound of formula 1, wherein the disease orcondition is associated with a kinase.

In accordance with the invention, the compounds of the invention may beused to treat diseases associated with undesired cellular proliferationor hyperproliferation comprising identifying the mammal afflicted withsaid disease or condition and administering to said afflicted mammal acomposition comprising the compound of formula 1, wherein the disease orcondition is associated with a tyrosine kinase.

In accordance with the invention, the compounds of the invention may beused to treat diseases associated with undesired cellular proliferationor hyperproliferation comprising identifying the mammal afflicted withsaid disease or condition and administering to said afflicted mammal acomposition comprising the compound of formula 1, wherein the disease orcondition is associated with the kinase that is a serine kinase or athreonine kinase.

In accordance with the invention, the compounds of the invention may beused to treat diseases associated with undesired cellular proliferationor hyperproliferation comprising identifying the mammal afflicted withsaid disease or condition and administering to said afflicted mammal acomposition comprising the compound of formula 1, wherein the disease orcondition is associated with the kinase that is a Src family kinase.

The invention also provides methods of treating a mammal afflicted withthe above diseases and conditions. The amount of the compounds of thepresent invention that may be combined with the carrier materials toproduce a composition in a single dosage form will vary depending uponthe host treated, the particular mode of administration. Preferably, thecompositions should be formulated so that a dosage of between 0.01-100mg/kg body weight/day of the inhibitor can be administered to a patientreceiving these compositions.

In one aspect, the invention compounds are administered in combinationwith chemotherapeutic agent, an anti-inflammatory agent, antihistamines,chemotherapeutic agent, immunomodulator, therapeutic antibody or aprotein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to asubject in need of such treatment.

The method includes administering one or more of the inventive compoundsto the afflicted mammal. The method may further include theadministration of a second active agent, such as a cytotoxic agent,including alkylating agents, tumor necrosis factors, intercalators,microtubulin inhibitors, and topoisomerase inhibitors. The second activeagent may be co-administered in the same composition or in a secondcomposition. Examples of suitable second active agents include, but arenot limited to, a cytotoxic drug such as Acivicin; Aclarubicin;Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin; Altretamine;Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine;Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa;Azotomycin; Batimastat; Benzodepa; Bicalutamide; BisantreneHydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate;Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone;Caracemide; Carbetimer; Carboplatin; Carmustine; CarubicinHydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin;Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine;Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine;Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel;Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; DroloxifeneCitrate; Dromostanolone Propionate; Duazomycin; Edatrexate; EflornithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride;Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate;Fluorouracil; Fluorocitabine; Fosquidone; Fostriecin Sodium;Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea;Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; InterferonBeta-□a; Interferon Gamma-Ib; Iproplatin; Irinotecan Hydrochloride;Lanreotide Acetate; Letrozole; Leuprolide Acetate; LiarozoleHydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride;Masoprocol; Maytansine; Mechlorethamine Hydrochloride; MegestrolAcetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine;Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide;Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper;Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole;Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan;Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium;Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol;Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium;Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin;Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; TeloxantroneHydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; TopotecanHydrochloride; Toremifene Citrate; Trestolone Acetate; TriciribinePhosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide;Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate;Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate;Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and ZorubicinHydrochloride.

In accordance with the invention, the compounds and compositions may beused at sub-cytotoxic levels in combination with other agents in orderto achieve highly selective activity in the treatment of non-neoplasticdisorders, such as heart disease, stroke and neurodegenerative diseases(Whitesell et al., Curr Cancer Drug Targets (2003), 3(5), 349-58).

The exemplary therapeutical agents that may be administered incombination with invention compounds include EGFR inhibitors, such asgefitinib, erlotinib, and cetuximab. Her2 inhibitors include canertinib,EKB-569, and GW-572016. Also included are Src inhibitors, dasatinib, aswell as Casodex (bicalutamide), Tamoxifen, MEK-1 kinase inhibitors, MARKkinase inhibitors, PI3 inhibitors, and PDGF inhibitors, such asimatinib, Hsp90 inhibitors, such as 17-AAG and 17-DMAG. Also includedare anti-angiogenic and antivascular agents which, by interrupting bloodflow to solid tumors, render cancer cells quiescent by depriving them ofnutrition. Castration, which also renders androgen dependent carcinomasnon-proliferative, may also be utilized. Also included are IGF1Rinhibitors, inhibitors of non-receptor and receptor tyrosine kineses,and inhibitors of integrin.

The pharmaceutical composition and method of the present invention mayfurther combine other protein therapeutic agents such as cytokines,immunomodulatory agents and antibodies. As used herein the term“cytokine” encompasses chemokines, interleukins, lymphokines, monokines,colony stimulating factors, and receptor associated proteins, andfunctional fragments thereof. As used herein, the term “functionalfragment” refers to a polypeptide or peptide which possesses biologicalfunction or activity that is identified through a defined functionalassay. The cytokines include endothelial monocyte activating polypeptideII (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF(G-CSF), macrophage-CSF (M-CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6,IL-12, and IL-13, interferons, and the like and which is associated witha particular biologic, morphologic, or phenotypic alteration in a cellor cell mechanism.

Other therapeutic agents for the combinatory therapy includecyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3,anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3),anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction betweenCD40 and gp39, such as antibodies specific for CD40 and for gpn39 (i.e.,CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG), cholesterolbiosynthesis inhibitors such as HM:G CoA reductase inhibitors(lovastatin and simvastatin), non-steroidal antiinflammatory drugs(NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such asrofecoxib, steroids such as prednisone or dexamethasone, gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprineand cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNFantibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof.

When other therapeutic agents are employed in combination with thecompounds of the present invention they may be used for example inamounts as noted in the Physician Desk Reference (PDR) or as otherwisedetermined by one having ordinary skill in the art.

EXAMPLES

The following examples are provided to further illustrate the presentinvention but, of course, should not be construed as in any way limitingits scope.

All experiments were performed under anhydrous conditions (i.e. drysolvents) in an atmosphere of argon, except where stated, usingoven-dried apparatus and employing standard techniques in handlingair-sensitive materials. Aqueous solutions of sodium bicarbonate(NaHCO3) and sodium chloride (brine) were saturated.

Analytical thin layer chromatography (TLC) was carried out on MerckKiesel gel 60 F254 plates with visualization by ultraviolet and/oranisaldehyde, potassium permanganate or phosphomolybdic acid dips.

NMR spectra: 1H Nuclear magnetic resonance spectra were recorded at 500MHz. Data are presented as follows: chemical shift, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, dd=doublet ofdoublets, m=multiplet, bs=broad singlet), coupling constant (J/Hz) andintegration. Coupling constants were taken and calculated directly fromthe spectra and are uncorrected.

Low resolution mass spectra: Electrospray (ES+) ionization was used. Theprotonated parent ion (M+H) or parent sodium ion (M+Na) or fragment ofhighest mass is quoted. Analytical gradient consisted of 10% ACN inwater ramping up to 100% ACN over 5 minutes unless otherwise stated.

Example 1

A mixture of ethyl β-ethoxyacrylate (26.50 g, 183 mmol) and 2 N sodiumhydroxide (110 mL, 220 mmol) was refluxed for 2 h and cooled to 0° C.water was removed under vacc., and the yellow solids were trituratedwith toluene and evaporated to give the sodium β-ethoxyacrylate (25 g,97%). The mixture of sodium β-thoxyacrylate (10.26 g, 74.29 mmol) andthionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporatedto give the β-ethoxyacryloyl chloride crude product, which was usedwithout purification. To a cold stirring solution of 3-ethoxyacryloylchloride in THF (100 mL) was added 2-chloro-6-methylaniline (6.2 mL,50.35 mmol) and pyridine (9 ml, 111 mmol). The mixture was then warmedand stirred overnight at room temperature. Water was added at 0-10° C.,extracted with EtOAc. The organic layer was washed with CuSO₄ (3×50 mL)and the resulting solution was passed a pad of silica gel, concentratedunder vacuum to give solids. The solids was diluted with toluene andkept at 0° C. The solid was collected by vacuum filtration, washed withwater and dried to give 5.2 g (43% yield) of compound 1,(E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). ¹H NMR (500 Hz,CDCl₃) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58(d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5Hz), 7.45 (d, 1H, J=12.4 Hz); ESI-MS: calcd for (C12H14ClNO2) 239, found240 MH⁺).

Example 2

To a mixture of compound 1 (5.30 g, 22.11 mmol) in 1,4-dioxane (100 mL)and water (70 mL) was added NBS (4.40 g, 24.72 mmol) at −10 to 0° C. Theslurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.85 g,26.16 mmol) was added and the mixture heated to 100° C. After 2 h, theresulting solution was cooled to 20-22° C. and conc. ammonium hydroxide(6 mL) was added dropwise. The resulting slurry was concentrated undervacuum to about half volume and cooled to 0-5° C. The solid wascollected by vacuum filtration, washed with cold water, and dried togive 5.4 g (90% yield) of compound 2 as deep-yellow solids. ¹H NMR (500MHz, DMSO-d₆) δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d,1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); ESI-MS: calcd for(C11H10ClN3OS) 267, found 268 MH⁺).

Example 3

A solution of methylmagnesium bromide in ether (3M, 30 ml, 90 mmole) wasadded dropwise to a stirred solution of cyanuric chloride (3.91 g, 21.20mmole) in anhydrous dichloromethane at −10° C. After the addition wascomplete, the reaction mixture was stirred at −5° C. for 4 h, afterwhich time water was added dropwise at a rate such that the temperatureof the reaction stayed below 10° C. After warming to room temperature,the reaction mixture was diluted with additional water and methylenechloride and passed through a pad of cilite. The organic layer was driedand evaporated to give 2,4-dichloro-6-methyl-1,3,5-triazine of 4 asyellow solids (3.02 g, 87%). ¹H NMR (CDCl³) δ 2.70 (s, 3H).

Example 4

A solution of Compound 3 (560 mg, 141 mmole), diisopropylamine (1.00 ml,5.74 mmole) and Compound 2 (700 mg, 2.65 mmole) in THF (40 mL) wasstirred at 0° C. for 30 min, then at room temperature for 2 hours. Waterwas added to the reaction mixture, and the aqueous mixture was extractedtwice with EtOAc. The combined extracts were washed with brine, dried,and evaporated in vacuo. Column chromatography provided Compound 4 aslight yellow solids (350 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ 2.19 (s,3H), 2.49 (s, 3H), 7.36-7.58 (m, 3H), 823 (br, 1H), 9.61 (br, 1H), 11.63(br, 1H); ESI-MS: calcd for (C15H12Cl2N6OS) 394, found 395 (MH⁺).

Example 5

A mixture of 4 (100 mg, 0.25 mmol), diisopropylethylamine (0.08 mL, 0.50mmol), and 1-(2-hydroxyethyl)piperazine (100 mg, 0.77 mmol) in1,4-dioxane (15 mL) was refluxed for 12 h. The mixture was concentratedunder vacuum, and water was added. The solid was collected byfiltration, triturated successively with H₂O, aqueous MeOH, and Et₂O(2×) and dried in vacuoto give 5 as light yellow solids (55 g, 45%). ¹HNMR (500 MHz, DMSO-d₆) δ11.97 (br s, 1H), 10.00 (s, 1H), 8.28 (s, 1H),7.40 (d, J=7.6 Hz, 1H), 7.29-7.24 (m, 2H), 4.45 (t, J=5.4 Hz, 1H),3.87-3.81 (m, 4H), 3.52 (q, J=6.0 Hz, 2H), 2.46 (m, 4H), 2.42 (t, J=6.0Hz, 2H), 2.30 (s, 3H), 2.23 (s, 3H). ESI-MS: calcd for (C21H25ClN8O2S)488, found 489 (MH⁺).

Example 6

Compound 6 was prepared by the same procedure as was used in thepreparation of Compound 5. Light yellow solids were obtained (42%yield). ESI-MS: calcd for (C24H24ClN9OS) 521, found 522 (MH⁺).

Example 7

-   -   (7)

Compound 7 was prepared by the same procedure as was used in thepreparation of Compound 5. Light yellow solids were obtained (92%yield). ESI-MS: calcd for (C20H23ClN8OS) 458, found 459 (MH⁺).

Example 8

Compound 8 was prepared by the same procedure as was used in thepreparation of Compound 5. Light yellow solids were obtained (94%yield). ESI-MS: calcd for (C19H20ClN7O2S) 445, found 446 (MH⁺).

Example 9

Compound 9 was prepared by the same procedure as was used in thepreparation of Compound 4. Light yellow solids were obtained (98%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 2.40 (s, 3H), 7.00 (d, J=8.9 Hz,2H), 7.07 (m, 2H), 7.41 (d, J=8.9 Hz, 2H), 7.63 (d, J=8.2 Hz, 1H), 7.72(d, J=8.5 Hz, 1H), 10.68 (br, 1H); ESI-MS: calcd for (C16H12Cl2N4O) 346,found 347 (MH⁺).

Example 10

Compound 10 was prepared by the same procedure as was used in thepreparation of Compound 5. White solids were obtained (91% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 9.64 (s, 1H), 7.73 (d, J=8.9 Hz, 2H), 7.40 (d,J=8.9 Hz, 2H), 7.01-6.96 (m, 4H), 4.45 (t, J=5.4 Hz, 1H), 3.73 (m, 4H),3.52 (q, J=6.1 Hz, 2H), 2.44 (m, 4H), 2.40 (t, J=6.3 Hz, 2H), 2.21 (s,3H). ESI-MS: calcd for (C22H25ClN6O2) 440, found 441 (MH⁺).

Example 11

Compound 11 was prepared by the same procedure as was used in thepreparation of Compound 5. White solids were obtained (96% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 9.69 (br, s, 1H), 8.17 (d, J=6.2 Hz, 2H), 7.75(d, J=8.9 Hz, 2H), 7.40 (d, J=8.9 Hz, 2H), 7.02-6.98 (m, 4H), 6.84 (d,J=6.2 Hz, 2H), 3.87 (m, 4H), 3.42 (m, 4H), 2.24 (s, 3H). ESI-MS: calcdfor (C25H24ClN7O) 473, found 474 (MH⁺).

Example 12

To a stirred solution of Compound 2 (100 mg, 0.37 mmole), and cyanuricchloride (35 mg, 0.19 mmole) in THF (5 mL) was added a solution ofsodium t-butoxide (125 mg, 1.30 mmol) in THF (1 mL) at 0° C. and themixture was stirred at room temperature for 1.5 h. Dilute HCl (1N, 1 mL)was added to the reaction mixture, and the mixture was concentrated.After filtration, the solids were washed by acetone, water, and dried togive Compound 12 as yellow solids (50 mg, 40%). ESI-MS: calcd for(C25H18Cl3N9O2S2) 645, found 646 (MH⁺).

Example 13

To a stirred solution of Compound 2 (200 mg, 0.75 mmole),diisopropylamine (0.26 ml, 1.49 mmole) and cyanuric chloride (134 mg,0.73 mmole) in THF (10 mL) was stirred at 0° C. for 1 h.2-hydroxyethyl-1-piperazine (100 mg, 0.77 mmole) was added at 0° C., andthe mixture was stirred at room temperature over night. Water was addedto the reaction mixture, and concentrated. After filtration, the solidswere washed by acetone, water, and dried to give Compound 13 as yellowsolids (200 mg, 52%). ESI-MS: calcd for (C20H22Cl2N8O2S) 508, found 509(MH⁺).

Example 14

To a stirred solution of Compound 3 (170 mg, 0.62 mmole),diisopropylamine (0.20 ml, 1.08 mmole) and cyanuric chloride (100 mg,0.54 mmole) in THF (10 mL) was stirred at 0° C. for 1 h.4-pyridyl-1-piperazine (180 mg, 1.10 mmole) was added at 0° C., and themixture was stirred at room temperature over night. Water was added tothe reaction mixture, and concentrated. After filtration, the solidswere washed by water, THF and dried to give Compound 14 as yellow solids(200 mg, 48%). ESI-MS: calcd for (C32H33ClN12OS) 668, found 669 (MH⁺).

Example 15

This example illustrated Src Kinase Assays of Compound 5 (referred toBoschelli et al., J. Med. Chem.; 2004; 47(7) pp 1599-1601). Briefly, Toestablish the appropriate enzyme concentration for inhibition assays,Src kinase (Upstate Cat 14-326, Lot 28234AU) was titrated and incubatedwith 25 μM Srctide peptide substrate (KVEKIGEGTYGVVY, where the tyrosinein bold designates the phosphorylated amino acid) and 50 μM ATP for 60minutes at 30° C. The phosphorylated product was detected using theHitHunter p34cdc2 EFC kinase assay (DiscoveRx, Product Code 90-0062, Lot06G2408).

Inhibitor IC50 values were determined by titration of compound at theoptimal kinase concentration (Kinase EC50). Identical assay conditionswere used as above and the effect of compound on kinase activitydetermined with the HitHunter EFC kinase assay (DiscoveRx).

FIG. 1 Inhibition of Src Kinase by Compound 5 Example 16

This example demonstrates the in vitro growth inhibition for certaincompounds of the invention on MX-1 (human breast carcinoma) cells.

A cytotoxicity assay was quantitated using the Promega CellTiter BlueCell Viability Assay. Briefly, cells (5000 cells/well) were plated onto96-well microtiter plates in RPMI 1640 medium supplemented with 10% FBSand incubated at 37° C. in a humidified 5% CO₂ atmosphere. After 24hrs., cells were exposed to various concentrations of compound in DMSOand cultured for another 72 hrs. 100 ul of media were removed and 20 ulof Promega CellTiter Blue reagent were added to each well and shaken tomix. After 4 hours of incubation at 37° C. in a humidified 5% CO₂atmosphere, the plates were read at 544 ex/620 em. The fluorescenceproduced is proportional to the number of viable cells. After plottingfluorescence produced against drug concentration, the IC₅₀ wascalculated as the half-life of the resulting non-linear regression. Thedata is presented in Table 2.

TABLE 1 Cytotoxicity of triazine derivatives Compound ID ChemicalStructure IC50 (μM) 4

12.2 5

16.0 6

2.6 7

38.7 8

58.1 9

19.1 10

14.1 11

1.4 12

237 13

171 14

131

1-27. (canceled)
 28. A method for treating a disease or condition in amammal characterized by undesired cellular proliferation orhyperproliferation comprising (a) identifying the mammal afflicted withsaid disease or condition and (b) administering to said afflicted mammala therapeutically effective amount of a composition comprising acompound or pharmaceutically acceptable form thereof selected from thegroup consisting of:


29. The method of claim 28, wherein the disease or condition is cancer,stroke, congestive heart failure, an ischemia or reperfusion injury,arthritis or other arthropathy, retinopathy or vitreoretinal disease,macular degeneration, autoimmune disease, vascular leakage syndrome,inflammatory disease, edema, transplant rejection, burn, or acute oradult respiratory distress syndrome.
 30. The method of claim 28, whereinthe disease or condition is cancer.
 31. The method of claim 28, whereinthe disease or condition is autoimmune disease.
 32. The method of claim28, wherein the disease or condition is stroke.
 33. The method of claim28, wherein the disease or condition is arthritis.
 34. The method ofclaim 28, wherein the disease or condition is inflammatory disease. 35.The method of claim 28, wherein the disease or condition is associatedwith a kinase.
 36. The method of claim 35, wherein the kinase is atyrosine kinase.
 37. The method of claim 35, wherein the kinase is aserine kinase or a threonine kinase.
 38. The method of claim 35, whereinthe kinase is a Src family kinase.
 39. The method of claim 30, whereinsaid-cancer is selected from the group consisting of cancers of theliver and biliary tree, intestinal cancers, colorectal cancer, ovariancancer, small cell and non-small cell lung cancer, breast cancer,sarcomas, fibrosarcoma, malignant fibrous histiocytoma, embryonalrhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, osteosarcoma,synovial sarcoma, liposarcoma, alveolar soft part sarcoma, neoplasms ofthe central nervous systems, brain, cancer, and lymphomas, includingHodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma,mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma,B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplasticlarge cell lymphoma, and combinations thereof.
 40. The method of claim28, further comprising administering to said afflicted mammal a saidsecond active agent selected from the group consisting of Acivicin;Aclarubicin; Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin;Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide;Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin;Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide;Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; BleomycinSulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin;Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; CarubicinHydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin;Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine;Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine;Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel;Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; DroloxifeneCitrate; Dromostanolone Propionate; Duazomycin; Edatrexate; EflomithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized OilI 131; Etoposide; Etoposide Phosphate; Etoprine; FadrozoleHydrochloride; Fazarabine; Fenretinide; Floxuridine; FludarabinePhosphate; Fluorouracil; Fluorocitabine; Fosquidone; Fostriecin Sodium;Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea;Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; InterferonBeta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride;Lanreotide Acetate; Letrozole; Leuprolide Acetate; LiarozoleHydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride;Masoprocol; Maytansine; Mechlorethamine Hydrochloride; MegestrolAcetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine;Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide;Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper;Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole;Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan;Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium;Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safmgol;Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium;Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin;Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; TeloxantroneHydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; TopotecanHydrochloride; Toremifene Citrate; Trestolone Acetate; TriciribinePhosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide;Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate;Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate;Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and ZorubicinHydrochloride.